期刊
ONCOGENE
卷 34, 期 11, 页码 1354-1362出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2014.76
关键词
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资金
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2009-1176023, 2011-0011365]
- NRF - Ministry of Science, ICT & Future Planning [2007-0054932]
- National Research Foundation of Korea [2011-0011365] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcription factor that has a central role in the regulation of tumour metabolism under hypoxic conditions. HIF-1 alpha stimulates glycolytic energy production and promotes tumour growth. Sirtuins are NAD(+)-dependent protein deacetylases that regulate cellular metabolism in response to stress; however, their involvement in the hypoxic response remains unclear. In this study, it is shown that SIRT2-mediated deacetylation of HIF-1 alpha regulates its stability in tumour cells. SIRT2 overexpression destabilized HIF-1 alpha under hypoxic conditions, whereas HIF-1 alpha protein levels were high in SIRT2-deficient cells. SIRT2 directly interacted with HIF-1 alpha and deacetylated Lys709 of HIF-1 alpha. Deacetylation of HIF-1 alpha by SIRT2 resulted in increased binding affinity for prolyl hydroxylase 2, a key regulator of HIF-1a stability, and increased HIF-1 alpha hydroxylation and ubiquitination. Moreover, a pharmacological agent that increased the intracellular NAD(+)/NADH ratio led to the degradation of HIF-1 alpha by increasing SIRT2-mediated deacetylation and subsequent hydroxylation. These findings suggest that SIRT2-mediated HIF-1 alpha deacetylation is critical for the destablization of HIF-1 alpha and the hypoxic response of tumour cells.
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